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J McCaffrey

Publications and source records attributed to J McCaffrey.

At least 19 recordsLinked to original sources
PubMed2006

Association between paclitaxel and necrotic pancreatitis.

To our knowledge this is the first reported case of paclitaxel associated necrotic pancreatitis requiring a pancreatic necrostomy. This was a near fatal complication associated with paclitaxel with a high resulting morbidity. Although this is a rare association physicians should be wary of the potential to develop severe pancreatitis in patients receiving this therapeautic agent. Monitoring of serum amylase during therapy is therefore warranted.

Adult↗
PubMed2001

Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer.

PURPOSE: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. PATIENTS AND METHODS: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m(2)), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. RESULTS: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m(2) without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. CONCLUSION: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.

Aged↗
PubMed2001

Men's attitudes toward prostate cancer and seeking prostate-specific antigen testing.

BACKGROUND: Although the Australian Cancer Society recommends against performing PSA tests to screen for prostate cancer, many Australian men currently undergo such screening. This study investigated attitudinal variables that may predict prostate cancer screening behaviors in this context. METHODS: A questionnaire was administered by mail in a two-phase procedure, first to a sample of 1,461 men (46% response), then to 919 men from the initial sample. Prostate cancer screening behaviors of men > 40 years old were examined. The questionnaire assessed worry about prostate cancer, perceived vulnerability to prostate cancer, belief in the efficacy of PSA testing for detection, having received a PSA test for detection, and the presence of urologic symptoms at the time of testing. RESULTS: Men who had had PSA testing with urologic symptoms at the time of the test were more worried about prostate cancer and perceived themselves as more vulnerable to prostate cancer compared with both asymptomatic tested and untested men. Men who had undergone PSA testing believed the test to be more effective in the detection of prostate cancer than did men who had not. CONCLUSIONS: Urologic symptoms act as a risk cue for men to prostate cancer. Asymptomatic men should be considered separately from symptomatic men in the investigation of psychological variables predictive of seeking screening for prostate cancer. These findings are discussed in terms of both the focus and design of interventions to alter prostate cancer screening behavior and their implications for the clinical management of men with urologic symptoms.

Adult↗
PubMed2000

Phase II trial of pyrazoloacridine in patients with cisplatin-refractory germ cell tumors.

Thirteen patients with cisplatin-refractory germ cell tumors were treated on a Phase II trial with pyrazoloacridine. Pyrazoloacridine was given intravenously at 600 mg/m2 every three weeks. The median nadir leucocyte count was 2.5 cells/mm3, hemoglobin was 10.8 g/dl, and platelet count was 126,000 cells/m3. None of the thirteen evaluable patients achieved a major response. Pyrazoloacridine is not efficacious in the treatment of cisplatin-refractory germ cell tumors.

Acridines↗
PubMed1999

Disruption of retinoblastoma protein family function by human papillomavirus type 16 E7 oncoprotein inhibits lens development in part through E2F-1.

Complexes between the retinoblastoma protein (pRb) and the transcription factor E2F-1 are thought to be important for regulating cell proliferation. We have shown previously that the E7 oncoprotein from human papillomavirus type 16, dependent upon its binding to pRb proteins, induces proliferation, disrupts differentiation, and induces apoptosis when expressed in the differentiating, or fiber, cells of the ocular lenses in transgenic mice. Mice that carry a null mutation in E2F-1 do not exhibit any defects in proliferation and differentiation in the lens. By examining the lens phenotype in mice that express E7 on an E2F-1 null background, we now show genetic evidence that E7's ability to alter the fate of fiber cells is partially dependent on E2F-1. On the other hand, E2F-1 status does not affect E7-induced proliferation in the undifferentiated lens epithelium. These data provide genetic evidence that E2F-1, while dispensible for normal fiber cell differentiation, is one mediator of E7's activity in vivo and that the requirement for E2F-1 is context dependent. These data suggest that an important role for pRb-E2F-1 complex during fiber cell differentiation is to negatively regulate cell cycle progression, thereby allowing completion of the differentiation program to occur.

Animals↗
PubMed1998

Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Certain forms of the heavy metals arsenic and chromium are considered human carcinogens, although they are believed to act through very different mechanisms. Chromium(VI) is believed to act as a classic and mutagenic agent, and DNA/chromatin appears to be the principal target for its effects. In contrast, arsenic(III) is considered nongenotoxic, but is able to target specific cellular proteins, principally through sulfhydryl interactions. We had previously shown that various genotoxic chemical carcinogens, including chromium (VI), preferentially altered expression of several inducible genes but had little or no effect on constitutive gene expression. We were therefore interested in whether these carcinogenic heavy metals might target specific but distinct sites within cells, leading to alterations in gene expression that might contribute to the carcinogenic process. Arsenic(III) and chromium(VI) each significantly altered both basal and hormone-inducible expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), at nonovertly toxic doses in the chick embryo in vivo and rat hepatoma H411E cells in culture. We have recently developed two parallel cell culture approaches for examining the molecular basis for these effects. First, we are examining the effects of heavy metals on expression and activation of specific transcription factors known to be involved in regulation of susceptible inducible genes, and have recently observed significant but different effects of arsenic(III) and chromium(VI) on nuclear transcription factor binding. Second, we have developed cell lines with stably integrated PEPCK promoter-luciferase reporter gene constructs to examine effects of heavy metals on promoter function, and have also recently seen profound effects induced by both chromium(VI) and arsenic(III) in this system. These model systems should enable us to be able to identify the critical cis (DNA) and trans (protein) cellular targets of heavy metal exposure leading to alterations in expression of specific susceptible genes. It is anticipated that such information will provide valuable insight into the mechanistic basis for these effects as well as provide sensitive molecular biomarkers for evaluating human exposure.

Animals↗
PubMed1997

Dose-dense therapy with paclitaxel via weekly 1-hour infusion: preliminary experience in the treatment of metastatic breast cancer.

In an ongoing effort to establish the most appropriate dose and administration schedule for paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the feasibility and safety of weekly 1-hour infusions were evaluated in 16 women with metastatic breast cancer previously treated with at least one chemotherapy regimen. Paclitaxel was administered on an outpatient basis at a starting dose of 100 mg/m2/wk for 4 consecutive weeks, with 4-week cycles continued until disease progression or the onset of intolerable toxicity. With 215 weekly infusions administered so far (median, 13 per patient), no episodes of febrile neutropenia have occurred, and no hematopoietic growth factors have been used. Plans for dose escalation were abandoned after grade 3 sensorimotor neuropathy developed in five of nine patients treated at paclitaxel 110 to 120 mg/m2. With dose escalation eliminated, further severe neurotoxicities were rare, but some degree of cumulative peripheral neuropathy was noted in all but three patients. No acute hypersensitivity reactions were noted. To date, six of 15 evaluable patients have achieved a major response to therapy, with one complete response and five partial responses. Four other patients had a minor response to therapy, one patient had an early death due to autopsy-proven extensive pulmonary microvascular carcinomatosis, and five patients have stable disease. Although the potential neurotoxicity of this regimen merits attention, the overall profile of a high therapeutic index, manageable toxicity, and convenient administration schedule makes this an attractive treatment alternative for patients with metastatic breast cancer.

Adult↗
PubMed1996

Red-Emitting Semiconductor Quantum Dot Lasers

Visible-stimulated emission in a semiconductor quantum dot (QD) laser structure has been demonstrated. Red-emitting, self-assembled QDs of highly strained InAlAs have been grown by molecular beam epitaxy on a GaAs substrate. Carriers injected electrically from the doped regions of a separate confinement heterostructure thermalized efficiently into the zero-dimensional QD states, and stimulated emission at approximately 707 nanometers was observed at 77 kelvin with a threshold current of 175 milliamperes for a 60-micrometer by 400-micrometer broad area laser. An external efficiency of approximately 8.5 percent at low temperature and a peak power greater than 200 milliwatts demonstrate the good size distribution and high gain in these high-quality QDs.

Journal Article↗
PubMed1994

Development regulation of basal and hormone-inducible phosphoenolpyruvate carboxykinase gene expression in chick embryo liver in vivo.

We have examined cytosolic phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) gene transcription and steady-state mRNA expression in chick embryo liver in vivo both constitutively and in response to dexamethasone, cAMP, retinoic acid, and the protein synthesis inhibitors, cycloheximide and pactamycin. We report here that PEPCK mRNA is constitutively expressed between 12 and 16 days of development. PEPCK expression was also transiently but highly inducible on Day 14 by dexamethasone, cAMP, cycloheximide, and pactamycin, but not by retinoic acid. Cycloheximide pretreatment had an additive or synergistic effect on the induction by dexamethasone and/or cAMP. Dexamethasone- and cycloheximide-induced increases in mRNA expression were principally due to increases in the rate of PEPCK gene transcription. Following an initial induction by dexamethasone, PEPCK expression was no longer responsive to a second administration of dexamethasone but was still responsive to cycloheximide and cAMP. PEPCK induction by dexamethasone or cycloheximide progressively diminished between 12 and 15 days of development. By Day 16, PEPCK expression was no longer responsive to dexamethasone, but was still inducible by cAMP and this induction was increased by cycloheximide. These results indicate that PEPCK is transiently inducible by glucocorticoids in chick embryo liver and that there are two developmental switches to the adult phenotype between Days 14 and 16 of development and between Day 16 and 4 days posthatching. Our results also suggest the presence of a developmentally regulated repressor of PEPCK gene expression in chick embryo liver.

Animals↗
PubMed1994

Comparison of effects of direct-acting DNA methylating and ethylating agents on inducible gene expression in vivo.

Our laboratory is interested in whether chemical carcinogen-induced DNA damage is non-randomly distributed in the genome, i.e., "targeted," at the level of individual genes. As one means of investigating this, we have examined whether carcinogen treatment differentially alters the expression of specific genes in vivo. In this study, we have compared the effects of four direct-acting simple alkylating agents (methyl methanesulfonate, ethyl methanesulfonate, methylnitrosourea, and ethylnitrosourea) on the steady-state mRNA expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), using the chick embryo as a simple in vivo test system. We observed no effect of any of these four carcinogens on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes in chick embryo liver following a single dose of carcinogen. In contrast, these same treatments significantly altered both the basal and inducible expression of the glucocorticoid-inducible PEPCK gene. These results support the hypothesis that inducible gene expression is a target for the effects of chemical carcinogens in vivo. In addition, the direction, magnitude, and time course of these effects were agent-specific. Qualitative and quantitative differences in effects between the methylating and ethylating agents and between the methanesulfonates and nitrosoureas were correlated with differences in their specific patterns of DNA adduct formation, suggesting that different DNA lesions have different effects on inducible gene expression.

Alkylating Agents↗
PubMed1994

Effects of the genotoxic carcinogen chromium(VI) on basal and hormone-inducible phosphoenolpyruvate carboxykinase gene expression in vivo: correlation with glucocorticoid- and developmentally regulated expression.

Previous studies have shown that a number of different genotoxic carcinogens that induce different types of DNA damage preferentially alter the expression of inducible genes in vivo. To investigate further the mechanistic basis for these effects, we examined the effects of the human lung carcinogen chromium(VI) on expression of the hormone-inducible cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene in chick embryo liver. Chromium(VI) pretreatment had significant effects on both basal and glucocorticoid-inducible PEPCK expression in 14-d-old embryo liver. These effects were principally a result of changes in PEPCK transcription. In contrast, treatment with chromium(VI) 1 h after treatment with glucocorticoid had no effect on PEPCK induction, suggesting that an early event in the induction process is the target for carcinogen effects. In 16-d-old liver, in which PEPCK expression is no longer responsive to glucocorticoid induction, both basal and inducible PEPCK expression were also refractory to chromium(VI) effects, indicating that carcinogen responsiveness is a phenotypic rather than an inherent property of inducible genes and is related to their competence for induction. Chromium(VI) had no effect on cAMP induction of PEPCK expression, demonstrating that carcinogens target their effects to specific regulatory pathways. Comparison of the effects of chromium(VI) with those of cycloheximide suggests that chromium(VI) targets its effects to a labile, constitutively expressed repressor involved in PEPCK gene regulation.

Animals↗
PubMed1991

Ethanol increases cytochromes P450IIE, IIB1/2, and IIIA in cultured rat hepatocytes.

In intact rats, ethanol treatment has been associated with increases in hepatic levels of both P450IIB1/2 and P450IIE. When rat hepatocytes were cultured on an extracellular tumor matrix (Matrigel), exposure to ethanol from 48 to 96 h in culture resulted in increases in cytochromes P450IIE, IIB1/2, and IIIA. Cytochrome P450IIE was detected immunologically and enzymatically, using two activities associated with cytochrome P450IIE, p-nitrophenol hydroxylation, and acetaminophen activation to a metabolite that binds to glutathione. The content of cytochrome P450IIE in freshly isolated cells decreased when the cells were placed in culture. Exposure of the cultured hepatocytes to ethanol from 48 to 96 h after inoculation resulted in an increase in cytochrome P450IIE compared to untreated cultured cells. In addition, in culture, the amount of enzymatically active protein after ethanol treatment was equal to that in hepatocytes freshly isolated from intact animals. Ethanol treatment resulted in increases in cytochrome P450IIB1/2 compared to untreated cells, as shown immunologically and by increased benzyloxyresorufin dealkylase activity. However, phenobarbital induced cytochrome P450IIB1/2 to higher levels, compared to ethanol. Ethanol and phenobarbital treatments both increased P450IIIA, as determined immunologically and by the amount of propoxycoumarin depropylase activity that is inhibited by triacetyloleandomycin. However, the amount of P450IIIA increased after ethanol treatment was less than that increased after treatment with dexamethasone in these cells. The ethanol-mediated increases in all four forms of cytochrome P450 in culture suggest that these increases in the intact animal result from direct effects of ethanol on the liver.

Acetaminophen↗
PubMed1990

Protective effects of voluntary exercise during the postinitiation phase of pancreatic carcinogenesis in the rat.

Studies were undertaken to evaluate the effects of exercise on the development of pancreatic cancer. Exercise is one life-style factor that has received little attention with regard to its role in the etiology of cancer. Male Lewis and female F344 rats were initiated with azaserine during the suckling period and weaned to the experimental protocols. Food and water were available ad libitum. A purified diet of 20% unsaturated fat was fed to both the sedentary and exercise groups. Rats of the exercise group had free access to voluntary exercise wheels. At approximately 2 and 4 months postinitiation, pancreases were evaluated for the number and size of azaserine-induced putative preneoplastic foci by quantitative stereology. Voluntary exercise activity peaked at approximately 2 months postinitiation with a gradual decline in activity there-after. Male Lewis rats averaged 0.95 +/- 0.13 km/day (SE) and female F344 rats averaged 2.73 +/- 0.26 km/day of voluntary wheel running. Compared with the sedentary groups, male Lewis and female F344 rats with access to the running wheels had significantly smaller foci at 4 months postinitiation. Azaserine-induced foci were evaluated in the male Lewis rats at both 2 and 4 months postinitiation. At 4 months postinitiation, the size and growth rate (as measured by [3H]thymidine autoradiography) of foci were less in the rats with access to the exercise wheels. No differences were observed at 2 months postinitiation. Access to voluntary exercise reduced the growth rate of azaserine-induced pancreatic foci. The effect occurred late in the postinitiation phase and was not directly related to the extent of running activity early in the postinitiation phase.

Animals↗